CA2889109C - Composition comprising citrulline and citicoline for improving decline in brain function - Google Patents
Composition comprising citrulline and citicoline for improving decline in brain function Download PDFInfo
- Publication number
- CA2889109C CA2889109C CA2889109A CA2889109A CA2889109C CA 2889109 C CA2889109 C CA 2889109C CA 2889109 A CA2889109 A CA 2889109A CA 2889109 A CA2889109 A CA 2889109A CA 2889109 C CA2889109 C CA 2889109C
- Authority
- CA
- Canada
- Prior art keywords
- decreased
- salt
- citrulline
- ability
- citicoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 title claims abstract description 91
- 229960002173 citrulline Drugs 0.000 title claims abstract description 78
- 229960001284 citicoline Drugs 0.000 title claims abstract description 72
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 235000013477 citrulline Nutrition 0.000 title claims abstract description 65
- 230000003925 brain function Effects 0.000 title claims abstract description 63
- 230000007423 decrease Effects 0.000 title claims abstract description 63
- RZZPDXZPRHQOCG-OJAKKHQRSA-M CDP-choline(1-) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-M 0.000 title claims abstract 8
- 239000000203 mixture Substances 0.000 title claims description 21
- 230000003247 decreasing effect Effects 0.000 claims abstract description 120
- 150000003839 salts Chemical class 0.000 claims abstract description 99
- 230000015654 memory Effects 0.000 claims abstract description 26
- 239000004480 active ingredient Substances 0.000 claims abstract description 20
- 230000008447 perception Effects 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 4
- 238000001356 surgical procedure Methods 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 210000002569 neuron Anatomy 0.000 abstract description 18
- 210000004556 brain Anatomy 0.000 abstract description 16
- 235000002639 sodium chloride Nutrition 0.000 description 90
- YWAFNFGRBBBSPD-OCMLZEEQSA-M sodium;[[(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 YWAFNFGRBBBSPD-OCMLZEEQSA-M 0.000 description 67
- 239000003795 chemical substances by application Substances 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 26
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 20
- -1 inorganic acid salts Chemical class 0.000 description 18
- 230000037406 food intake Effects 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 11
- 230000006399 behavior Effects 0.000 description 11
- 230000001976 improved effect Effects 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000004475 Arginine Substances 0.000 description 8
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 8
- 235000009697 arginine Nutrition 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000006872 improvement Effects 0.000 description 7
- 238000004806 packaging method and process Methods 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000019634 flavors Nutrition 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000035899 viability Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 230000000971 hippocampal effect Effects 0.000 description 5
- 230000002269 spontaneous effect Effects 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000011302 passive avoidance test Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical class NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000001168 carotid artery common Anatomy 0.000 description 3
- 230000003727 cerebral blood flow Effects 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000016273 neuron death Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012549 training Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- RHGKLRLOHDJJDR-SCSAIBSYSA-N D-citrulline Chemical compound OC(=O)[C@H](N)CCCNC(N)=O RHGKLRLOHDJJDR-SCSAIBSYSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 229940064004 antiseptic throat preparations Drugs 0.000 description 2
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 2
- 229940045145 uridine Drugs 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- PJVXUVWGSCCGHT-ZPYZYFCMSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;(3s,4r,5r)-1,3,4,5,6-pentahydroxyhexan-2-one Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO PJVXUVWGSCCGHT-ZPYZYFCMSA-N 0.000 description 1
- DROVUXYZTXCEBX-WCCKRBBISA-N (2s)-2-amino-5-(carbamoylamino)pentanoic acid;2-hydroxybutanedioic acid Chemical compound OC(=O)C(O)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=O DROVUXYZTXCEBX-WCCKRBBISA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 102100027715 4-hydroxy-2-oxoglutarate aldolase, mitochondrial Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- RZZPDXZPRHQOCG-OJAKKHQRSA-N CDP-choline Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- PCDQPRRSZKQHHS-CCXZUQQUSA-N Cytarabine Triphosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 PCDQPRRSZKQHHS-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 239000004265 EU approved glazing agent Substances 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241001071795 Gentiana Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Chemical class OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 240000004670 Glycyrrhiza echinata Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 101001081225 Homo sapiens 4-hydroxy-2-oxoglutarate aldolase, mitochondrial Proteins 0.000 description 1
- 101000974007 Homo sapiens Nucleosome assembly protein 1-like 3 Proteins 0.000 description 1
- 101001099181 Homo sapiens TATA-binding protein-associated factor 2N Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical class OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical class NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Chemical class 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102100022398 Nucleosome assembly protein 1-like 3 Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 101100094105 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) NPL6 gene Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000003935 attention Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Chemical class OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 201000008191 cerebritis Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000010326 executive functioning Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 235000007144 ferric diphosphate Nutrition 0.000 description 1
- 239000011706 ferric diphosphate Substances 0.000 description 1
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 description 1
- 229940036404 ferric pyrophosphate Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001879 hippocampal ca1 region Anatomy 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 230000006993 memory improvement Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical class OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000011273 social behavior Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000004143 urea cycle Effects 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An object of the present invention is to provide an agent for preventing or improving decline in brain function such as decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby. According to the present invention, an agent for protecting brain neuronal cells, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients as well as an agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients is provided.
Description
DESCRIPTION
COMPOSITION COMPRISING CITRULLINE AND CITICOLINE FOR
IMPROVING DECLINE IN BRAIN FUNCTION
Technical Field The present invention relates to an agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients.
Background Art Brain is the most significant region of central nerve system for information transmission via nerves such as motion and perception, and plays an important role in human mental activity such as feelings, emotions, reasoning or the like.
Higher brain dysfunctions caused by cerebral trauma, cerebrovascular disorders, cerebritis, hypoxia or the like include a wide range of defects in memory, attention, executive functioning, social behavior and the like, and their characteristics vary depending on the part of the brain damage. Further, it is also reported that decline in brain function can be caused by fatigue (Non-Patent Literature 1), leading to decline in abilities such as memory learning, attention concentration, judgment or the like.
It is known that ischemic cerebrovascular disease causes brain neuronal cell death, leading to decline in brain function. The cause includes neurovascular damage, endothelial dysfunction, diminished cerebral blood flow or the like (Non-Patent Literature
COMPOSITION COMPRISING CITRULLINE AND CITICOLINE FOR
IMPROVING DECLINE IN BRAIN FUNCTION
Technical Field The present invention relates to an agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients.
Background Art Brain is the most significant region of central nerve system for information transmission via nerves such as motion and perception, and plays an important role in human mental activity such as feelings, emotions, reasoning or the like.
Higher brain dysfunctions caused by cerebral trauma, cerebrovascular disorders, cerebritis, hypoxia or the like include a wide range of defects in memory, attention, executive functioning, social behavior and the like, and their characteristics vary depending on the part of the brain damage. Further, it is also reported that decline in brain function can be caused by fatigue (Non-Patent Literature 1), leading to decline in abilities such as memory learning, attention concentration, judgment or the like.
It is known that ischemic cerebrovascular disease causes brain neuronal cell death, leading to decline in brain function. The cause includes neurovascular damage, endothelial dysfunction, diminished cerebral blood flow or the like (Non-Patent Literature
2), and it is understood that a reduction of normal nitric oxide (NO) production in vascular endothelial cells and diminished cerebral blood flow cause brain neuronal cell death and decline in brain function. In other words, it is expected that brain neuronal cells can be protected and decline in brain function can be prevented or improved by enhancing NO production in vascular endothelial cells and cerebral blood flow.
Citrulline is one of amino acids present as free form and is not used as a
Citrulline is one of amino acids present as free form and is not used as a
3 0 constituent for protein synthesis in vivo. In the body, citrulline serves as a precursor of arginine in arginine biosynthesis or an important component of NO cycle involved in NO
supply. Ingested citrulline is mostly converted to arginine in the kidney and produced arginine is efficiently supplied systemically (Non-Patent Literature 3).
Arginine is an amino acid to be a direct substrate of nitric oxide (NO) synthase.
Moreover, arginine is an intermediate in the urea cycle in the liver, and plays an important role in detoxication of ammonia produced in the body. NO synthesized from arginine as a substrate exerts a variety of physiological functions for maintaining normal vascular functions, including vasodilatation, inhibition of LDL
oxidation, inhibition of platelet aggregation, anti-proliferation effect on smooth muscle cells, antioxidant effect and the like.
It is reported that ingestion of citrulline shows an anti-arteriosclerosis action and improves blood circulation via the production of the vasodilator NO (Non-Patent Literature 4), and citrulline is widely used around US as a food material for producing NO to improve blood circulation. Citrulline is also used in Europe as an anti-fatigue drug in the form of citrulline-malate.
Citicoline is a water-soluble substance that is biosynthesized from choline phosphate and cytidine triphosphate in animals, yeasts or the like. Citicoline is involved in the biosynthesis of phosphatidylcholine which is a component of cell membrane, acetylcholine which is a neurotransmitter, or the like. It is also reported that citicoline, once orally ingested, is degraded into choline and uridine during intestinal absorption, and citicoline is reconstituted in the brain (Non-Patent Literature 5).
It is reported that ingestion of citicoline improves prognosis of acute cerebral infarction (Non-Patent Literature 6), cognitive function in Alzheimer's-type dementia (Non-Patent Literature 7) or the like. Owing to these functions, citicoline has been used as a medicine for the improvement of brain metabolism, impaired consciousness and pancreatitis in Japan and as a food material for the improvement or amelioration of brain function in foreign countries.
Until now, there have been reports about improvement of attention concentration by oral ingestion of citrulline (Patent Literature 1) and improvement of memory learning ability by intraperitoneal injection of arginine (Non-Patent Literature 8). However, there have been no reports that a synergistic effect of preventing or improving decline in brain function can be obtained by using citrulline or a salt thereof in combination with citicoline or a salt thereof Citation List Patent Literature [PTL1] WO 2009/096505 Non Patent Literature [NPL1] Journal of occupational health, 2007, Vol.49, p.203-208 [NPL2] Neuroscience. 1999, Vol.91, p.203-210 [NPL3] Amino Acids, 2005, Vol.29, p.177-205 -NPL41 PNAS, 2005, Vol.102, p.13681-13686 [NPL5] Journal of Neuroscience Research, 1999, Vol.58-5, p.697-705 [NPL6] Stroke, 2002. Vol.33, p.2850-2857 -_NPL7] Methods and findings in experimental and clinical pharmacology, 1999, Vol.21-9, p.633-644 [NPL8] Psychopharmacology, 2003, Vol.167, p.291-296 Summary of Invention Technical Problem An objection of the present invention is to provide an agent for preventing or improving decline in brain function such as decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise perfoimance caused thereby.
Solution to Problem The present invention relates to the following (1) to (13):
(1) An agent for protecting brain neuronal cells, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients.
(2) An agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients.
(3) The agent for preventing or improving decline in brain function described in (2), wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
supply. Ingested citrulline is mostly converted to arginine in the kidney and produced arginine is efficiently supplied systemically (Non-Patent Literature 3).
Arginine is an amino acid to be a direct substrate of nitric oxide (NO) synthase.
Moreover, arginine is an intermediate in the urea cycle in the liver, and plays an important role in detoxication of ammonia produced in the body. NO synthesized from arginine as a substrate exerts a variety of physiological functions for maintaining normal vascular functions, including vasodilatation, inhibition of LDL
oxidation, inhibition of platelet aggregation, anti-proliferation effect on smooth muscle cells, antioxidant effect and the like.
It is reported that ingestion of citrulline shows an anti-arteriosclerosis action and improves blood circulation via the production of the vasodilator NO (Non-Patent Literature 4), and citrulline is widely used around US as a food material for producing NO to improve blood circulation. Citrulline is also used in Europe as an anti-fatigue drug in the form of citrulline-malate.
Citicoline is a water-soluble substance that is biosynthesized from choline phosphate and cytidine triphosphate in animals, yeasts or the like. Citicoline is involved in the biosynthesis of phosphatidylcholine which is a component of cell membrane, acetylcholine which is a neurotransmitter, or the like. It is also reported that citicoline, once orally ingested, is degraded into choline and uridine during intestinal absorption, and citicoline is reconstituted in the brain (Non-Patent Literature 5).
It is reported that ingestion of citicoline improves prognosis of acute cerebral infarction (Non-Patent Literature 6), cognitive function in Alzheimer's-type dementia (Non-Patent Literature 7) or the like. Owing to these functions, citicoline has been used as a medicine for the improvement of brain metabolism, impaired consciousness and pancreatitis in Japan and as a food material for the improvement or amelioration of brain function in foreign countries.
Until now, there have been reports about improvement of attention concentration by oral ingestion of citrulline (Patent Literature 1) and improvement of memory learning ability by intraperitoneal injection of arginine (Non-Patent Literature 8). However, there have been no reports that a synergistic effect of preventing or improving decline in brain function can be obtained by using citrulline or a salt thereof in combination with citicoline or a salt thereof Citation List Patent Literature [PTL1] WO 2009/096505 Non Patent Literature [NPL1] Journal of occupational health, 2007, Vol.49, p.203-208 [NPL2] Neuroscience. 1999, Vol.91, p.203-210 [NPL3] Amino Acids, 2005, Vol.29, p.177-205 -NPL41 PNAS, 2005, Vol.102, p.13681-13686 [NPL5] Journal of Neuroscience Research, 1999, Vol.58-5, p.697-705 [NPL6] Stroke, 2002. Vol.33, p.2850-2857 -_NPL7] Methods and findings in experimental and clinical pharmacology, 1999, Vol.21-9, p.633-644 [NPL8] Psychopharmacology, 2003, Vol.167, p.291-296 Summary of Invention Technical Problem An objection of the present invention is to provide an agent for preventing or improving decline in brain function such as decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise perfoimance caused thereby.
Solution to Problem The present invention relates to the following (1) to (13):
(1) An agent for protecting brain neuronal cells, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients.
(2) An agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients.
(3) The agent for preventing or improving decline in brain function described in (2), wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
(4) A method for preventing or improving decline in brain function, wherein citrulline or a salt thereof and citicoline or a salt thereof are orally ingested as active ingredients.
(5) A method for preventing or improving decline in brain function, wherein an oral preparation comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients is ingested.
(6) A method for preventing or improving decline in brain function, wherein citrulline or a salt thereof and citicoline or a salt thereof are orally ingested as active ingredients, provided that the prevention or improvement method does not include any method of surgery, therapy or diagnosis of humans practiced by medical doctor.
(7) A method for preventing or improving decline in brain function, wherein an oral preparation comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients is ingested, provided that the prevention or improvement method does not include any method of surgery, therapy or diagnosis of humans practiced by medical doctor.
(8) Citrulline or a salt thereof and citicoline or a salt thereof for use in protecting brain neuronal cells.
(9) Citrulline or a salt thereof and citicoline or a salt thereof for use in preventing or improving decline in brain function.
(10) The citrulline or a salt thereof and the citicoline or a salt thereof described in (9), wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
(11) Use of citrulline or a salt thereof and citicoline or a salt thereof for the manufacture of an agent for protecting brain neuronal cells.
(12) Use of citrulline or a salt thereof and citicoline or a salt thereof for the manufacture of an agent for preventing or improving decline in brain function.
(13) The use described in (12), wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance 3 0 caused thereby.
According to an aspect, the invention relates to a composition for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to another aspect, the invention relates to a use, for preventing or improving decline in brain function, of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to yet another aspect, the invention relates to a use, for preventing or improving decline in brain function, of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the use excludes any method of surgery, therapy or diagnosis of humans practiced by a medical doctor, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to yet another aspect, the invention relates to a composition comprising citrulline or a salt thereof and citicoline or a salt thereof, for use in preventing or improving decline in brain function, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to yet another aspect, the invention relates to a use of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof, for the manufacture of a medicament for preventing or improving decline in brain function, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
4a In the above aspects of the invention, the composition or medicament is orally ingestable.
Advantageous Effects of Invention 4b According to the present invention, a safe and effective agent for protecting brain neuronal cells and a safe and effective agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients can be provided. According to the agent of the present invention, memory behavior can be synergistically and effectively improved by using citrulline or a salt thereof in combination with citicoline or a salt thereof, and excellent effect as the agent for preventing or improving decline in brain function can be obtained.
Brief Description of Drawings FIG. 1 shows spontaneous alternation behavior rate (Alternation) in the Y-maze test after administration of each concentration of the sample to mice for 7 days.
Mean d standard error. N = 4 to 6. There are significant differences between different letters.
FIG. 2 shows the time spent in the light compartment (Latency time) in the passive avoidance test after administration of each concentration of the sample to mice for 7 days. Mean standard error. N = 4 to 6. There are significant differences (p <
0.05) between different letters.
FIG. 3 shows a ratio of the frequency of exploring the familiar and novel objects in the novel object recognition test after administration of each concentration of the sample to mice for 7 days. Mean standard error. N = 4 to 6. ** indicates significant differences (p <0.01) between the familiar and novel objects.
FIG. 4 shows the viability of hippocampal nerve cells after administration of each concentration of the sample to mice for 12 days. Mean standard error. N
= 8.
There are significant differences (p <0.05) between different letters.
Description of Embodiments Citrulline used in the present invention includes L-citrulline and D-citrulline.
Preferred is L-citrulline. Citrulline can be obtained by chemical synthesis, fermentation or the like. Citrulline can be also obtained by purchasing a commercially available product. A chemical synthesis method of citrulline includes the methods described in J.
Biol. Chem., 122, 477(1938) and J. Org. Chem., 6, 410(1941).
A method for producing L-citrulline by fermentation includes the methods described in Japanese Patent Publication Nos. 1978-075387 and 1988-068091. In addition, L-citrulline and D-citrulline can also be purchased from Sigma-Aldrich Co., or the like.
The salts of citrulline include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The acid addition salt includes inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and the like, and organic acid salts such as acetate, maleate, fumarate, citrate, malate, lactate, a-ketoglutarate, gluconate, caprylate and the like. The metal salt includes alkali metal salts such as sodium salts, potassium salts and the like, alkaline earth metal salts such as magnesium salts, calcium salts and the like, aluminum salts, zinc salts and the like. The ammonium salt includes ammonium salts, tetramethylammonium salts and the like. The organic amine addition salt includes morpholine salts, piperidine salts and the like. The amino acid addition salt includes salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like. Among the above-mentioned salts of citrulline, malate is preferably used. Other salts or two or more salts may be used in an appropriate combination.
Citicoline (citidine-5'-diphosphocholine (CDP-choline)) used in the present invention may be those obtained by any production method. The production method for citicoline includes the chemical synthesis (Japanese Patent Publication Nos.
1964-6541, 1967-1384, 1988-6558, and the like), the enzymatic method using a microorganism such as yeast or the like (Japanese Patent Publication Nos. 1973-2358, 1973-40757, 1973-40758, 1978-109996, 1979-14593, 1988-313594, etc.) or the like.
Citicoline can be also purchased from Sigma-Aldrich Co., or the like.
The citicoline comprised in the agent for preventing or improving decline in brain function of the present invention may exist as a salt thereof in the agent. The salt 2 5 of citicoline includes the same salt as that of citrulline as mentioned above.
In the present invention, a compound involved in the synthesis of citicoline in vivo, for example, choline, uridine, or the like can be also used instead of citicoline.
A composition ratio of citrulline or a salt thereof to citicolinc or a salt thereof in the agent for preventing or improving decline in brain function of the present invention is 1:100 to 100:1, preferably 1:50 to 50:1, particularly preferably 10:1 to 1:10 by weight.
As the agent for preventing or improving decline in brain function of the present invention, citrulline or a salt thereof and citicoline or a salt thereof can be administered as such, but it is usually preferred to provide the agent as various kinds of preparations.
The preparations comprise, as active ingredients, citrulline or a salt thereof and citicoline or a salt thereof and further may include any active ingredients.
The .. preparations are produced according to any methods well known in the technical field of pharmaceutics by mixing the active ingredients with one or more kinds of pharmaceutically acceptable carriers.
Administration routes of the preparation may include oral administration and parenteral administration such as intravenous administration, intraperitoneal administration, subcutaneous administration or the like. Preferred is oral administration.
The preparation may be administered either in the form of oral preparations such as tablets, powders, granules, pills, suspensions, emulsions, infusions/decoctions, capsules, syrups, liquids, elixirs, extracts, tinctures, fluid extracts and the like, or parenteral preparations such as injections, drops, creams, suppositories and the like.
Preferred are oral preparations.
Liquid preparations suitable for oral administration such as syrups can be prepared by adding water, sugars such as sucrose, sorbitol, fructose or the like, glycols such as polyethylene glycol, propylene glycol or the like, oils such as sesame oil, olive oil, soybean oil or the like, antiseptics such as p-hydroxybenzoate ester or the like, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate or the like, flavors such as strawberry flavor, peppermint or the like, or the like.
For example, tablets, powders, granules, or the like suitable for oral administration can be prepared by adding excipients such as sugars such as lactose, 2 5 white sugar, glucose, sucrose, mannitol, sorbitol or the like, starch such as potato, wheat, corn or the like, inorganic substances such as calcium carbonate, calcium sulfate, sodium hydrogen carbonate, sodium chloride or the like, plant powders such as crystalline cellulose, licorice powder, powdered gentian or the like, disintegrating agents such as starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium hydrogen carbonate, sodium alginate or the like, lubricants such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil or the like, binders such as polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carmellose, gelatin, starch paste or the like, surfactants such as fatty acid esters or the like, plasticizers such as glycerin or the like.
The preparations suitable for oral ingestion or administration includes additives generally used in foods such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color developers, bleaching agents, fungicides, gum bases, bitter agents, enzymes, glazing agents, sour agents, seasonings, emulsifiers, enhancers, manufacture facilitating agents, flavors, spice extracts and the like.
The product forms or preparations suitable for oral ingestion or administration may be processed to, for example, tablets, powders, granules, pills, suspensions, 1 0 emulsions, infusions/decoctions, capsules, drinks, liquids, elixirs, extracts, tinctures, or fluid extracts in a unit packaging form per ingestion, depending on ingestion period, ingestion frequency, ingestion dose and the like. For example, "unit packaging form per ingestion" means that a pre-determined amount is packaged for each ingestion, and "unit packaging form for 1 week to 3 months" means that an ingestion dose for 1 week to 3 months is packaged. Examples of the unit packaging form include a form for prescribing a predetermined amount, such as a pack, a package, a bottle and the like.
With respect to the "unit packaging form per ingestion", for example, if the product form or preparation is a drink, 50 mg or more of citrulline or a salt thereof and citicoline or a salt thereof suspended or dissolved in a drink may be all packaged in a bottle for one ingestion.
With respect to the "unit packaging form for 1 week to 3 months", for example, it is ingested once a day to give a daily ingestion dose of 300 mg, 50 mg of citrulline or a salt thereof and citicoline or a salt thereof are contained in a tablet, and 42 to 540 tablets are packaged in each packaging foim.
With respect to preparations suitable for parenteral administration, for example, injections preferably comprise a sterilized aqueous preparation containing citrulline or a salt thereof and citicoline or a salt thereof, which is isotonic to the recipient's blood. In the case of an injection, for example, a solution for injection is prepared using a carrier containing a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
One or more of auxiliary components selected from the above-described antiseptics, preservatives, excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers and the like for oral preparations can also be employed in these parenteral preparations.
The concentrations of citrulline or a salt thereof and citicoline or a salt thereof in the agent for preventing or improving decline in brain function of the present invention are appropriately determined according to the kind of the preparation, the effect expected by the administration of the preparation or the like.
Citrulline or a salt thereof is usually contained in an amount of 0.1 to 90% by weight, preferably 0.5 to 70% by weight, particularly preferably 1 to 50% by weight. Citicoline or a salt thereof is usually contained in an amount of 0.1 to 90% by weight, preferably 0.5 to 70% by weight, particularly preferably 1 to 50% by weight.
The administration dose and administration frequency of the agent for preventing or improving decline in brain function of the present invention vary depending on the administration form, the patient's age and body weight, and the characteristics or severity of the symptoms to be treated. Usually, the agent is administered once to several times per day in an amount to give a daily dose of 50 mg to 30 g, preferably 100 mg to10 g, particularly preferably 200 mg to 3 g per adult in terms of citrulline or a salt thereof. Further, usually, the agent is administered once to several times per day in an amount to give a daily dose of 50 mg to 30 g, preferably 100 mg to10 g, particularly preferably 200 mg to 3 g per adult in terms of citicoline or a salt thereof Ingestion or administration period is not particularly limited, but it is generally 1 day to 1 year, preferably 1 week to 3 months.
The agent for preventing or improving decline in brain function of the present invention can be used for protecting brain neuronal cells. The agent for preventing or improving decline in brain function of the present invention can be used for preventing or improving decline in brain function that is developed from brain neuronal cell death.
Examples of the effects expected by preventing or improving decline in brain function includes prevention or improvement of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, decreased cognitive function and decreased exercise performance caused thereby.
Therefore, the agent for preventing or improving decline in brain function of the present invention is administered to a subject in need of preventing occurrence of these symptoms or a subject having these symptoms, thereby preventing or improving the symptoms.
Further, in the present invention, citrulline or a salt thereof and citicoline or a salt thereof may be used in order to manufacture the agent for preventing or improving decline in brain function.
Further, the present invention includes a method for protecting brain neuronal cells. The method of the present invention comprises the step of ingesting or administering citrulline or a salt thereof and citicoline or a salt thereof to a subject in need of protecting the brain neuronal cells in amounts sufficient to protect the brain neuronal cells of the subject.
Further, the present invention includes a method for preventing or improving decline in brain function. The method of the present invention includes the step of ingesting or administering citrulline or a salt thereof and citicoline or a salt thereof to a subject in need of preventing or improving decline in brain function, in amounts sufficient to prevent or improve decline in brain function of the subject.
Hereinafter, Experimental Examples regarding citrulline and citicoline for preventing or improving decline in brain function will be described.
Experimental Example: 10-week-old male C57BL/6J mice (CLEA Japan, Inc.
approximately 25 g of average body weight per mouse) were preliminarily acclimated for 1 week, and provided for experiments. L-citrulline and citicoline were obtained from KYOWA HAKKO BIO CO., LTD.
C57BL/6.1 mice were divided into a sham-operation group (Group 1) and a bilateral common carotid arteries occlusion group, which was performed under halothane anesthesia for 20 minutes. One day after reperfusion, the bilateral common carotid arteries occlusion group was further divided into a distilled water-treated group (Group 2), a low-dose L-citrulline-treated group (40 mg/kg: Group 3), a low-dose citicoline-treated group (40 mg/kg: Group 4), a high-dose L-citrulline-treated group (100 mg/kg: Group 5), a high-dose citicoline-treated group (100 mg/kg: Group 6), and a combination treatment group of a low dose of L-citrulline and a low dose of citicoline (each 40 mg/kg: Group 7). Each sample was orally administered for 12 days. One week after starting administration, learning memory-improving effects were examined by a Y-maze test, a passive avoidance test, and a novel object recognition test. After evaluating learning memory functions, the hippocampus was removed and viability of hippocampal nerve cells was evaluated.
Y-maze test In the Y-maze test, a Y-maze apparatus with three arms (50x16x32 cm) was used. Mice were placed at any one arm of the Y-maze and were allowed to explore freely through the maze for 8 minutes. The sequence of arm entries was recorded. The number of entries into each arm was counted during the measurement time, which was defined as the total number of entries. Of them, the successive entry into the three different arms was examined, and this number was defined as the spontaneous 1 0 alternation behavior number. The spontaneous alternation behavior number was divided by (the total number of arm entries minus two), and then multiplied by 100, which was defined as the spontaneous alternation behavior rate (Alternation) and used as an index for spontaneous alternation behavior.
As shown in FIG. 1, a low Alternation was observed in Group 2, compared to .. Group 1. Compared to Group 2, a high Alternation was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which Alternation cannot be improved. An improved effect of memory behavior was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Passive avoidance test The passive avoidance test was performed using a box consisting of dark (25x25x25 cm) and light compartments (14x10x25 cm) and being equipped with an electrical stimulation apparatus at the bottom of the dark compartment. During training, as soon as the mouse entered the dark compartment from the light compartment, the door was closed, and an electrical stimulation (0.3 mA, for 2 seconds) was delivered.
Twenty four hours after training, the mouse was placed again in the light compartment, and the latency time spent in the light compartment was recorded with a maximum latency of 300 seconds.
As shown in FIG. 2, a significantly low latency time was observed in Group 2, compared to Group 1. Compared to Group 2, a high latency time was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which the latency time cannot be improved. An improved effect of memory behavior was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Novel object recognition test The novel object recognition test was performed after mice were individually acclimated to the open field apparatus (35 x25 x35 cm) for 2 days. During training, mice were allowed to explore freely for 10 minutes in an apparatus where two identical objects were symmetrically placed. After 1 hour, one object was replaced by a novel object, and mice were allowed to explore freely for 5 minutes. Object exploration was defined as standing on the objects, touching the object with the nose, or sniffing the object within 1 cm from the object. A ratio of the frequency of exploring the familiar or novel object over the total exploration frequency was calculated, and used as an index for visual recognition memory.
As shown in FIG. 3, the increase in the frequency of exploring the novel object observed in Group 1 was not observed in Group 2. A significant increase in the frequency of exploring the novel object was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which the frequency of exploring the novel object cannot be increased. A remarkably improved effect of memory behavior was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Evaluation of viability of hippocampal nerve cells Twelve days after bilateral occlusion of the common carotid arteries, mice were anesthetized with pentobarbital sodium, and perfused with ice-cold phosphate buffer (PBS, pH 7.4) until the blood in the body was completely removed. immediately, mice .. were perfused with a fixative solution containing 4% paraformaldehyde. The brain tissues were fixed at 4 C for 24 hours, and coronal sections having a thickness of 50 i.tm were prepared. Serial sections containing the hippocampus were stained with propidium iodide (PI, 5 mon) dissolved in PBS and observed under a fluorescent microscope. Surviving and non-surviving nerve cells in the CA1 pyramidal cell layer of the hippocampus were counted at 1.4 to 1.8 mm posterior to bregma, and cells with PI-positive nuclei and typical morphological characteristics were defined as surviving nerve cells. The cell viability was calculated from a ratio to the average number of surviving nerve cells in Group 1.
As shown in FIG. 4, a significant reduction in the viability of hippocampal neurons was observed in Group 2, compared to Group 1. Compared to Group 2, a significantly high viability of hippocampal nerve cells was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which the viability of hippocampal nerve cells cannot be improved. A nerve cell-protecting effect was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Taken together, it was clarified that the memory behavior can be synergistically and effectively improved by using citrulline in combination with citicoline, suggesting that the agent of the present invention is excellent in the prevention or improvement of decline in brain function.
Hereinafter, Examples of the present invention will be described.
[Example 1]
Preparation of tablet containing citrulline and citicoline 120 kg of L-citrulline, 120 kg of citicoline, 19 kg of cyclic oligosaccharide, kg of cellulose, and 1 kg of pullulan were granulated using a fluid bed granulator dryer.
The granulated product thus obtained and 3 kg of calcium stearate were mixed using a conical blender, and compression-molded in a rotary compression molding machine to give a tablet.
[Example 2]
Preparation of enteric tablet containing citrulline and citicoline The surface of the tablet prepared in Example 1 was coated with a shellac solution to give an enteric tablet.
[Example 31 Preparation of enteric capsule containing citrulline and citicoline 120 kg of L-citrulline, 120 kg of citicoline, 19 kg of cyclic oligosaccharide, kg of cellulose, 3 kg of calcium stearate and 1 kg of pullulan were mixed using a conical blender. 20 kg of the obtained mixture and 0.2 kg of silicon dioxide were mixed and stirred, The obtained mixture was fed into a capsule filling machine, and filled in hard capsules to give a hard capsule. The surface of the obtained hard capsule was coated with a zein solution to give an enteric capsule.
[Example 4]
Preparation of drink containing citrulline and citicoline (1) 1.28 kg of L-citrulline, 1.28 kg of citicoline, 3 kg of erythritol, 0.05 kg of citric acid, 3 g of artificial sweetener, and 0.06 kg of flavor were dissolved in 50 L of water at 70 C under stirring, and the solution was adjusted to pH 3.3 with citric acid. The mixture was sterilized by plate sterilization and filled in a bottle. Then, the bottle is sterilized by pasteurizer to give a drink.
[Example 5]
Preparation of drink containing citrulline and citicoline (2) 20 mg of L-citrulline, 20 mg of citicoline, 20 mg of L-arginine, a proper amount of fructose glucose syrup, salt, citric acid, flavor, Na citrate, Ca lactate, ferric pyrophosphate, Ca gluconate, K chloride, Mg chloride, and a sweetener were blended to give a 555 mL of drink.
[Example 6]
Preparation of drink containing citrulline and citicoline (3) 100 mg of L-citrulline, 100 mg of citicoline, 100 mg of L-arginine, 2.5 mg of L-alanine, 2.5 mg of L-glycine, 2.5 mg of L-leucine, 1.3 mg of L-isoleucine, 1.3 mg of L-valine and a proper amount of a flavor and a sweetener were blended to give a 300 ml of drink.
Industrial Applicability According to the present invention, an agent for preventing or improving decline in brain function such as decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients is provided. According to the agent of the present invention, memory behavior can be synergistically and effectively improved by using citrulline or a salt thereof in combination with citicoline or a salt thereof, and excellent effect as the agent for preventing or improving decline in brain function can be obtained.
According to an aspect, the invention relates to a composition for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to another aspect, the invention relates to a use, for preventing or improving decline in brain function, of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to yet another aspect, the invention relates to a use, for preventing or improving decline in brain function, of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the use excludes any method of surgery, therapy or diagnosis of humans practiced by a medical doctor, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to yet another aspect, the invention relates to a composition comprising citrulline or a salt thereof and citicoline or a salt thereof, for use in preventing or improving decline in brain function, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
According to yet another aspect, the invention relates to a use of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof, for the manufacture of a medicament for preventing or improving decline in brain function, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
4a In the above aspects of the invention, the composition or medicament is orally ingestable.
Advantageous Effects of Invention 4b According to the present invention, a safe and effective agent for protecting brain neuronal cells and a safe and effective agent for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients can be provided. According to the agent of the present invention, memory behavior can be synergistically and effectively improved by using citrulline or a salt thereof in combination with citicoline or a salt thereof, and excellent effect as the agent for preventing or improving decline in brain function can be obtained.
Brief Description of Drawings FIG. 1 shows spontaneous alternation behavior rate (Alternation) in the Y-maze test after administration of each concentration of the sample to mice for 7 days.
Mean d standard error. N = 4 to 6. There are significant differences between different letters.
FIG. 2 shows the time spent in the light compartment (Latency time) in the passive avoidance test after administration of each concentration of the sample to mice for 7 days. Mean standard error. N = 4 to 6. There are significant differences (p <
0.05) between different letters.
FIG. 3 shows a ratio of the frequency of exploring the familiar and novel objects in the novel object recognition test after administration of each concentration of the sample to mice for 7 days. Mean standard error. N = 4 to 6. ** indicates significant differences (p <0.01) between the familiar and novel objects.
FIG. 4 shows the viability of hippocampal nerve cells after administration of each concentration of the sample to mice for 12 days. Mean standard error. N
= 8.
There are significant differences (p <0.05) between different letters.
Description of Embodiments Citrulline used in the present invention includes L-citrulline and D-citrulline.
Preferred is L-citrulline. Citrulline can be obtained by chemical synthesis, fermentation or the like. Citrulline can be also obtained by purchasing a commercially available product. A chemical synthesis method of citrulline includes the methods described in J.
Biol. Chem., 122, 477(1938) and J. Org. Chem., 6, 410(1941).
A method for producing L-citrulline by fermentation includes the methods described in Japanese Patent Publication Nos. 1978-075387 and 1988-068091. In addition, L-citrulline and D-citrulline can also be purchased from Sigma-Aldrich Co., or the like.
The salts of citrulline include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The acid addition salt includes inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and the like, and organic acid salts such as acetate, maleate, fumarate, citrate, malate, lactate, a-ketoglutarate, gluconate, caprylate and the like. The metal salt includes alkali metal salts such as sodium salts, potassium salts and the like, alkaline earth metal salts such as magnesium salts, calcium salts and the like, aluminum salts, zinc salts and the like. The ammonium salt includes ammonium salts, tetramethylammonium salts and the like. The organic amine addition salt includes morpholine salts, piperidine salts and the like. The amino acid addition salt includes salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like. Among the above-mentioned salts of citrulline, malate is preferably used. Other salts or two or more salts may be used in an appropriate combination.
Citicoline (citidine-5'-diphosphocholine (CDP-choline)) used in the present invention may be those obtained by any production method. The production method for citicoline includes the chemical synthesis (Japanese Patent Publication Nos.
1964-6541, 1967-1384, 1988-6558, and the like), the enzymatic method using a microorganism such as yeast or the like (Japanese Patent Publication Nos. 1973-2358, 1973-40757, 1973-40758, 1978-109996, 1979-14593, 1988-313594, etc.) or the like.
Citicoline can be also purchased from Sigma-Aldrich Co., or the like.
The citicoline comprised in the agent for preventing or improving decline in brain function of the present invention may exist as a salt thereof in the agent. The salt 2 5 of citicoline includes the same salt as that of citrulline as mentioned above.
In the present invention, a compound involved in the synthesis of citicoline in vivo, for example, choline, uridine, or the like can be also used instead of citicoline.
A composition ratio of citrulline or a salt thereof to citicolinc or a salt thereof in the agent for preventing or improving decline in brain function of the present invention is 1:100 to 100:1, preferably 1:50 to 50:1, particularly preferably 10:1 to 1:10 by weight.
As the agent for preventing or improving decline in brain function of the present invention, citrulline or a salt thereof and citicoline or a salt thereof can be administered as such, but it is usually preferred to provide the agent as various kinds of preparations.
The preparations comprise, as active ingredients, citrulline or a salt thereof and citicoline or a salt thereof and further may include any active ingredients.
The .. preparations are produced according to any methods well known in the technical field of pharmaceutics by mixing the active ingredients with one or more kinds of pharmaceutically acceptable carriers.
Administration routes of the preparation may include oral administration and parenteral administration such as intravenous administration, intraperitoneal administration, subcutaneous administration or the like. Preferred is oral administration.
The preparation may be administered either in the form of oral preparations such as tablets, powders, granules, pills, suspensions, emulsions, infusions/decoctions, capsules, syrups, liquids, elixirs, extracts, tinctures, fluid extracts and the like, or parenteral preparations such as injections, drops, creams, suppositories and the like.
Preferred are oral preparations.
Liquid preparations suitable for oral administration such as syrups can be prepared by adding water, sugars such as sucrose, sorbitol, fructose or the like, glycols such as polyethylene glycol, propylene glycol or the like, oils such as sesame oil, olive oil, soybean oil or the like, antiseptics such as p-hydroxybenzoate ester or the like, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate or the like, flavors such as strawberry flavor, peppermint or the like, or the like.
For example, tablets, powders, granules, or the like suitable for oral administration can be prepared by adding excipients such as sugars such as lactose, 2 5 white sugar, glucose, sucrose, mannitol, sorbitol or the like, starch such as potato, wheat, corn or the like, inorganic substances such as calcium carbonate, calcium sulfate, sodium hydrogen carbonate, sodium chloride or the like, plant powders such as crystalline cellulose, licorice powder, powdered gentian or the like, disintegrating agents such as starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium hydrogen carbonate, sodium alginate or the like, lubricants such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil or the like, binders such as polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carmellose, gelatin, starch paste or the like, surfactants such as fatty acid esters or the like, plasticizers such as glycerin or the like.
The preparations suitable for oral ingestion or administration includes additives generally used in foods such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, color developers, bleaching agents, fungicides, gum bases, bitter agents, enzymes, glazing agents, sour agents, seasonings, emulsifiers, enhancers, manufacture facilitating agents, flavors, spice extracts and the like.
The product forms or preparations suitable for oral ingestion or administration may be processed to, for example, tablets, powders, granules, pills, suspensions, 1 0 emulsions, infusions/decoctions, capsules, drinks, liquids, elixirs, extracts, tinctures, or fluid extracts in a unit packaging form per ingestion, depending on ingestion period, ingestion frequency, ingestion dose and the like. For example, "unit packaging form per ingestion" means that a pre-determined amount is packaged for each ingestion, and "unit packaging form for 1 week to 3 months" means that an ingestion dose for 1 week to 3 months is packaged. Examples of the unit packaging form include a form for prescribing a predetermined amount, such as a pack, a package, a bottle and the like.
With respect to the "unit packaging form per ingestion", for example, if the product form or preparation is a drink, 50 mg or more of citrulline or a salt thereof and citicoline or a salt thereof suspended or dissolved in a drink may be all packaged in a bottle for one ingestion.
With respect to the "unit packaging form for 1 week to 3 months", for example, it is ingested once a day to give a daily ingestion dose of 300 mg, 50 mg of citrulline or a salt thereof and citicoline or a salt thereof are contained in a tablet, and 42 to 540 tablets are packaged in each packaging foim.
With respect to preparations suitable for parenteral administration, for example, injections preferably comprise a sterilized aqueous preparation containing citrulline or a salt thereof and citicoline or a salt thereof, which is isotonic to the recipient's blood. In the case of an injection, for example, a solution for injection is prepared using a carrier containing a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
One or more of auxiliary components selected from the above-described antiseptics, preservatives, excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers and the like for oral preparations can also be employed in these parenteral preparations.
The concentrations of citrulline or a salt thereof and citicoline or a salt thereof in the agent for preventing or improving decline in brain function of the present invention are appropriately determined according to the kind of the preparation, the effect expected by the administration of the preparation or the like.
Citrulline or a salt thereof is usually contained in an amount of 0.1 to 90% by weight, preferably 0.5 to 70% by weight, particularly preferably 1 to 50% by weight. Citicoline or a salt thereof is usually contained in an amount of 0.1 to 90% by weight, preferably 0.5 to 70% by weight, particularly preferably 1 to 50% by weight.
The administration dose and administration frequency of the agent for preventing or improving decline in brain function of the present invention vary depending on the administration form, the patient's age and body weight, and the characteristics or severity of the symptoms to be treated. Usually, the agent is administered once to several times per day in an amount to give a daily dose of 50 mg to 30 g, preferably 100 mg to10 g, particularly preferably 200 mg to 3 g per adult in terms of citrulline or a salt thereof. Further, usually, the agent is administered once to several times per day in an amount to give a daily dose of 50 mg to 30 g, preferably 100 mg to10 g, particularly preferably 200 mg to 3 g per adult in terms of citicoline or a salt thereof Ingestion or administration period is not particularly limited, but it is generally 1 day to 1 year, preferably 1 week to 3 months.
The agent for preventing or improving decline in brain function of the present invention can be used for protecting brain neuronal cells. The agent for preventing or improving decline in brain function of the present invention can be used for preventing or improving decline in brain function that is developed from brain neuronal cell death.
Examples of the effects expected by preventing or improving decline in brain function includes prevention or improvement of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, decreased cognitive function and decreased exercise performance caused thereby.
Therefore, the agent for preventing or improving decline in brain function of the present invention is administered to a subject in need of preventing occurrence of these symptoms or a subject having these symptoms, thereby preventing or improving the symptoms.
Further, in the present invention, citrulline or a salt thereof and citicoline or a salt thereof may be used in order to manufacture the agent for preventing or improving decline in brain function.
Further, the present invention includes a method for protecting brain neuronal cells. The method of the present invention comprises the step of ingesting or administering citrulline or a salt thereof and citicoline or a salt thereof to a subject in need of protecting the brain neuronal cells in amounts sufficient to protect the brain neuronal cells of the subject.
Further, the present invention includes a method for preventing or improving decline in brain function. The method of the present invention includes the step of ingesting or administering citrulline or a salt thereof and citicoline or a salt thereof to a subject in need of preventing or improving decline in brain function, in amounts sufficient to prevent or improve decline in brain function of the subject.
Hereinafter, Experimental Examples regarding citrulline and citicoline for preventing or improving decline in brain function will be described.
Experimental Example: 10-week-old male C57BL/6J mice (CLEA Japan, Inc.
approximately 25 g of average body weight per mouse) were preliminarily acclimated for 1 week, and provided for experiments. L-citrulline and citicoline were obtained from KYOWA HAKKO BIO CO., LTD.
C57BL/6.1 mice were divided into a sham-operation group (Group 1) and a bilateral common carotid arteries occlusion group, which was performed under halothane anesthesia for 20 minutes. One day after reperfusion, the bilateral common carotid arteries occlusion group was further divided into a distilled water-treated group (Group 2), a low-dose L-citrulline-treated group (40 mg/kg: Group 3), a low-dose citicoline-treated group (40 mg/kg: Group 4), a high-dose L-citrulline-treated group (100 mg/kg: Group 5), a high-dose citicoline-treated group (100 mg/kg: Group 6), and a combination treatment group of a low dose of L-citrulline and a low dose of citicoline (each 40 mg/kg: Group 7). Each sample was orally administered for 12 days. One week after starting administration, learning memory-improving effects were examined by a Y-maze test, a passive avoidance test, and a novel object recognition test. After evaluating learning memory functions, the hippocampus was removed and viability of hippocampal nerve cells was evaluated.
Y-maze test In the Y-maze test, a Y-maze apparatus with three arms (50x16x32 cm) was used. Mice were placed at any one arm of the Y-maze and were allowed to explore freely through the maze for 8 minutes. The sequence of arm entries was recorded. The number of entries into each arm was counted during the measurement time, which was defined as the total number of entries. Of them, the successive entry into the three different arms was examined, and this number was defined as the spontaneous 1 0 alternation behavior number. The spontaneous alternation behavior number was divided by (the total number of arm entries minus two), and then multiplied by 100, which was defined as the spontaneous alternation behavior rate (Alternation) and used as an index for spontaneous alternation behavior.
As shown in FIG. 1, a low Alternation was observed in Group 2, compared to .. Group 1. Compared to Group 2, a high Alternation was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which Alternation cannot be improved. An improved effect of memory behavior was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Passive avoidance test The passive avoidance test was performed using a box consisting of dark (25x25x25 cm) and light compartments (14x10x25 cm) and being equipped with an electrical stimulation apparatus at the bottom of the dark compartment. During training, as soon as the mouse entered the dark compartment from the light compartment, the door was closed, and an electrical stimulation (0.3 mA, for 2 seconds) was delivered.
Twenty four hours after training, the mouse was placed again in the light compartment, and the latency time spent in the light compartment was recorded with a maximum latency of 300 seconds.
As shown in FIG. 2, a significantly low latency time was observed in Group 2, compared to Group 1. Compared to Group 2, a high latency time was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which the latency time cannot be improved. An improved effect of memory behavior was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Novel object recognition test The novel object recognition test was performed after mice were individually acclimated to the open field apparatus (35 x25 x35 cm) for 2 days. During training, mice were allowed to explore freely for 10 minutes in an apparatus where two identical objects were symmetrically placed. After 1 hour, one object was replaced by a novel object, and mice were allowed to explore freely for 5 minutes. Object exploration was defined as standing on the objects, touching the object with the nose, or sniffing the object within 1 cm from the object. A ratio of the frequency of exploring the familiar or novel object over the total exploration frequency was calculated, and used as an index for visual recognition memory.
As shown in FIG. 3, the increase in the frequency of exploring the novel object observed in Group 1 was not observed in Group 2. A significant increase in the frequency of exploring the novel object was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which the frequency of exploring the novel object cannot be increased. A remarkably improved effect of memory behavior was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Evaluation of viability of hippocampal nerve cells Twelve days after bilateral occlusion of the common carotid arteries, mice were anesthetized with pentobarbital sodium, and perfused with ice-cold phosphate buffer (PBS, pH 7.4) until the blood in the body was completely removed. immediately, mice .. were perfused with a fixative solution containing 4% paraformaldehyde. The brain tissues were fixed at 4 C for 24 hours, and coronal sections having a thickness of 50 i.tm were prepared. Serial sections containing the hippocampus were stained with propidium iodide (PI, 5 mon) dissolved in PBS and observed under a fluorescent microscope. Surviving and non-surviving nerve cells in the CA1 pyramidal cell layer of the hippocampus were counted at 1.4 to 1.8 mm posterior to bregma, and cells with PI-positive nuclei and typical morphological characteristics were defined as surviving nerve cells. The cell viability was calculated from a ratio to the average number of surviving nerve cells in Group 1.
As shown in FIG. 4, a significant reduction in the viability of hippocampal neurons was observed in Group 2, compared to Group 1. Compared to Group 2, a significantly high viability of hippocampal nerve cells was observed in Group 7 that is a combination group of Group 3 and Group 4, in each of which the viability of hippocampal nerve cells cannot be improved. A nerve cell-protecting effect was recognized in Group 7, equivalent to those of Group 5 and Group 6.
Taken together, it was clarified that the memory behavior can be synergistically and effectively improved by using citrulline in combination with citicoline, suggesting that the agent of the present invention is excellent in the prevention or improvement of decline in brain function.
Hereinafter, Examples of the present invention will be described.
[Example 1]
Preparation of tablet containing citrulline and citicoline 120 kg of L-citrulline, 120 kg of citicoline, 19 kg of cyclic oligosaccharide, kg of cellulose, and 1 kg of pullulan were granulated using a fluid bed granulator dryer.
The granulated product thus obtained and 3 kg of calcium stearate were mixed using a conical blender, and compression-molded in a rotary compression molding machine to give a tablet.
[Example 2]
Preparation of enteric tablet containing citrulline and citicoline The surface of the tablet prepared in Example 1 was coated with a shellac solution to give an enteric tablet.
[Example 31 Preparation of enteric capsule containing citrulline and citicoline 120 kg of L-citrulline, 120 kg of citicoline, 19 kg of cyclic oligosaccharide, kg of cellulose, 3 kg of calcium stearate and 1 kg of pullulan were mixed using a conical blender. 20 kg of the obtained mixture and 0.2 kg of silicon dioxide were mixed and stirred, The obtained mixture was fed into a capsule filling machine, and filled in hard capsules to give a hard capsule. The surface of the obtained hard capsule was coated with a zein solution to give an enteric capsule.
[Example 4]
Preparation of drink containing citrulline and citicoline (1) 1.28 kg of L-citrulline, 1.28 kg of citicoline, 3 kg of erythritol, 0.05 kg of citric acid, 3 g of artificial sweetener, and 0.06 kg of flavor were dissolved in 50 L of water at 70 C under stirring, and the solution was adjusted to pH 3.3 with citric acid. The mixture was sterilized by plate sterilization and filled in a bottle. Then, the bottle is sterilized by pasteurizer to give a drink.
[Example 5]
Preparation of drink containing citrulline and citicoline (2) 20 mg of L-citrulline, 20 mg of citicoline, 20 mg of L-arginine, a proper amount of fructose glucose syrup, salt, citric acid, flavor, Na citrate, Ca lactate, ferric pyrophosphate, Ca gluconate, K chloride, Mg chloride, and a sweetener were blended to give a 555 mL of drink.
[Example 6]
Preparation of drink containing citrulline and citicoline (3) 100 mg of L-citrulline, 100 mg of citicoline, 100 mg of L-arginine, 2.5 mg of L-alanine, 2.5 mg of L-glycine, 2.5 mg of L-leucine, 1.3 mg of L-isoleucine, 1.3 mg of L-valine and a proper amount of a flavor and a sweetener were blended to give a 300 ml of drink.
Industrial Applicability According to the present invention, an agent for preventing or improving decline in brain function such as decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients is provided. According to the agent of the present invention, memory behavior can be synergistically and effectively improved by using citrulline or a salt thereof in combination with citicoline or a salt thereof, and excellent effect as the agent for preventing or improving decline in brain function can be obtained.
14
Claims (9)
1. A composition for preventing or improving decline in brain function, comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
2. The composition according to claim 1, which is orally ingestable.
3. Use, for preventing or improving decline in brain function, of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
4. Use for preventing or improving decline in brain function, of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof as active ingredients, wherein the use excludes any method of surgery, therapy or diagnosis of humans practiced by a medical doctor, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
5. The use according to claim 3 or 4, wherein the composition is orally ingestable.
6. A composition comprising citrulline or a salt thereof and citicoline or a salt thereof, for use in preventing or improving decline in brain function, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
7. The composition according to claim 6, which is orally ingestable.
8. Use of a composition comprising citrulline or a salt thereof and citicoline or a salt thereof, for the manufacture of a medicament for preventing or improving decline in brain function, wherein the decline in brain function is one or more selected from the group consisting of decreased perception ability, decreased memory learning ability, decreased thinking ability, decreased concentration, decreased attention, decreased judgment ability, depression, and decreased exercise performance caused thereby.
9. The use according to claim 8, wherein the medicament is orally ingestable.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012238542 | 2012-10-30 | ||
JP2012-238542 | 2012-10-30 | ||
PCT/JP2013/080053 WO2014069667A1 (en) | 2012-10-30 | 2013-10-30 | Agent for preventing or improving decline in brain function |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2889109A1 CA2889109A1 (en) | 2014-05-08 |
CA2889109C true CA2889109C (en) | 2020-09-01 |
Family
ID=50627559
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2889109A Active CA2889109C (en) | 2012-10-30 | 2013-10-30 | Composition comprising citrulline and citicoline for improving decline in brain function |
Country Status (9)
Country | Link |
---|---|
US (2) | US10905705B2 (en) |
EP (1) | EP2914270B1 (en) |
JP (1) | JP6166786B2 (en) |
AU (1) | AU2013339058B2 (en) |
CA (1) | CA2889109C (en) |
ES (1) | ES2906614T3 (en) |
NZ (1) | NZ707081A (en) |
PL (1) | PL2914270T3 (en) |
WO (1) | WO2014069667A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ707081A (en) | 2012-10-30 | 2019-03-29 | Kyowa Hakko Bio Co Ltd | Agent for preventing or improving decline in brain function |
WO2015166463A1 (en) | 2014-04-30 | 2015-11-05 | Kyowa Hakko Bio Co., Ltd. | Administration of citicoline to improve cognitive performance, attentional performance, and motor function |
CN117069780A (en) | 2016-10-06 | 2023-11-17 | 协和发酵生化株式会社 | Crystal of cytidine diphosphate choline and method for producing same |
JP7142284B2 (en) * | 2017-06-06 | 2022-09-27 | 株式会社らいむ | Nerve elongation promoter |
JP2019218284A (en) * | 2018-06-18 | 2019-12-26 | オンガネジャパン株式会社 | Oral composition for improving juvenile learning ability, and method for improving juvenile learning ability |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT813416E (en) * | 1995-03-06 | 2005-10-31 | Interneuron Pharma | REDUCING VOLUME OF FUNGUS USING CITICOLIN |
US20010056068A1 (en) * | 1998-03-04 | 2001-12-27 | Kristof Chwalisz | Method of treatment and prevention of nitric oxide deficiency-related disorders with citrulline and citrulline derivatives |
US20060046982A1 (en) | 2004-08-26 | 2006-03-02 | Waugh William H | Orthomolecular medical use of L-citrulline for capillary endothelial protection and adjacent cell protection in neurodegenerative disease |
JP5931325B2 (en) * | 2008-01-30 | 2016-06-08 | 協和発酵バイオ株式会社 | Attention concentration improver |
JP2012517421A (en) * | 2009-02-11 | 2012-08-02 | ライカ ラブズ リミテッド | Liposome citicoline injection |
ES2345802B1 (en) * | 2009-03-30 | 2011-09-08 | Hospital Clinic I Provincial De Barcelona | PHARMACEUTICAL COMPOSITION FOR NEUROPROTECTOR TREATMENT IN PATIENTS WITH ICTUS. |
NZ707081A (en) | 2012-10-30 | 2019-03-29 | Kyowa Hakko Bio Co Ltd | Agent for preventing or improving decline in brain function |
-
2013
- 2013-10-30 NZ NZ707081A patent/NZ707081A/en unknown
- 2013-10-30 WO PCT/JP2013/080053 patent/WO2014069667A1/en active Application Filing
- 2013-10-30 ES ES13850415T patent/ES2906614T3/en active Active
- 2013-10-30 JP JP2015538829A patent/JP6166786B2/en active Active
- 2013-10-30 EP EP13850415.4A patent/EP2914270B1/en active Active
- 2013-10-30 AU AU2013339058A patent/AU2013339058B2/en active Active
- 2013-10-30 PL PL13850415T patent/PL2914270T3/en unknown
- 2013-10-30 CA CA2889109A patent/CA2889109C/en active Active
- 2013-10-30 US US14/435,984 patent/US10905705B2/en active Active
-
2020
- 2020-12-30 US US17/138,742 patent/US11738037B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
US20150306125A1 (en) | 2015-10-29 |
EP2914270B1 (en) | 2022-01-12 |
ES2906614T3 (en) | 2022-04-19 |
CA2889109A1 (en) | 2014-05-08 |
AU2013339058B2 (en) | 2017-09-07 |
EP2914270A4 (en) | 2016-03-16 |
US20210113601A1 (en) | 2021-04-22 |
JP6166786B2 (en) | 2017-07-19 |
NZ707081A (en) | 2019-03-29 |
JP2015535241A (en) | 2015-12-10 |
AU2013339058A1 (en) | 2015-05-07 |
US10905705B2 (en) | 2021-02-02 |
PL2914270T3 (en) | 2022-03-14 |
EP2914270A1 (en) | 2015-09-09 |
WO2014069667A1 (en) | 2014-05-08 |
US11738037B2 (en) | 2023-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11738037B2 (en) | Agent for preventing or improving decline in brain function | |
EP3320895B1 (en) | Rapid-acting, blood-arginine-level-increasable oral preparation comprising citrulline and arginine | |
ES2458353T3 (en) | Preparation comprising amino acids and plants and their activity in alcohol detoxification and in the treatment of migraine | |
US7932288B2 (en) | Composition for relieving subjective symptoms of fatigue | |
JP5085541B2 (en) | Fatigue reducing agent | |
KR20100094485A (en) | Anti-fatigue agent comprising amino acid composition | |
US11654125B2 (en) | Agent for elevating nitric oxide concentration | |
JP5931325B2 (en) | Attention concentration improver | |
AU2013219258B2 (en) | Agent for preventing or ameliorating vascular endothelial malfunction | |
JP2013060406A (en) | Oral agent for brain fatigue improvement | |
AU2013339057B2 (en) | Agent for preventing or improving decline in brain function | |
JP2016121194A (en) | Oral agent for cerebral fatigue improvement | |
JP6533784B2 (en) | Eye fatigue improver | |
US20150216925A1 (en) | Agent for preventing or ameliorating vascular endothelial malfunction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20181009 |